The purpose of this K23 Mentored Patient-Oriented Research Career Development Award application is to support my short-term career objective of integrating multimodal neuroimaging and genetic techniques in the study of cognitive and behavioral differences in young girls with Turner syndrome (TS). TS is characterized by the complete or partial loss of an X chromosome. The neurocognitive phenotype may be characterized by deficits in visuospatial, executive function and social cognition domains. These impairments have a significant impact on adaptive functioning in affected individuals. Previous neuroimaging studies in TS have largely limited investigation to individuals with complete X-monosomy. Therefore, the research proposed here will be one of the first to identify structural and white matter brain differences in young girls with the mosaic karyotype of TS (moTS). Specifically, neuropsychological assessments, structural magnetic resonance imaging and diffusion imaging methods, will be used to investigate neuroanatomical substrates in young girls with moTS. Our hypotheses predict that volumetric and white matter differences will be observed in regions correlated to: (1) visuospatial skills - including parietal and occipital corties and frontal-parietal pathways, (2) executive function - including frontal cortex and prefrontal-striatal-parietal pathways, and (3) social cognition - including amygdala, orbitofrontal, fusiform and superior temporal regions and related pathways. Furthermore, we will investigate a putative 'dosage' effect of X chromosome genes on brain structure and behavior, by elucidating the effect of mosaicism on severity of neurocognitive phenotype in individuals with moTS. Understanding the influence of mosaicism in TS relative to typical development will allow enhanced understanding of the role of the X chromosome in cognitive-behavioral development and inform future development of preventative and treatment strategies for this disorder. My previous clinical work with children with developmental disorders, and neuroimaging experience in individuals with monosomic karyotype of TS, have laid a solid foundation for helping me achieve these aims. However, I propose to gain further expertise in incorporating sophisticated neuroimaging methods, genomics and statistics to enhance these skills. The proposed integrated research, mentorship and didactic training programs, combined with the outstanding research environment at Stanford University will foster my long-term career objective to be an independent investigator studying gene, brain and behavior interactions in childhood neurodevelopmental syndromes. PUBLIC HEALTH RELEVANCE: There has been limited investigation of cognition, behavior and neuroanatomy in young girls with the mosaic karyotype of Turner syndrome. Innovative approaches are required to define a conceptual framework of X chromosome influence on brain and behavior. The proposed research will help identify genetic factors that may ultimately improve long-term outcomes for children with Turner syndrome.